Overview and State of the Art in the Management of Lung Cancer

Overview and State of the Art in the Management of Lung Cancer

ABSTRACT: Lung cancer is a major health problem worldwide. Non–small-cell
lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers,
while small-cell lung cancer (SCLC) accounts for 15% to 20% of cases.
For early-stage and locally advanced NSCLC (stages I through III), a
multimodality treatment approach is appropriate because it improves
survival. Combination chemotherapy is currently the standard treatment
for good performance patients with metastatic disease. Elderly
patients (≥ 70 years) with metastatic NSCLC also benefit from treatment.
In SCLC, concurrent radiation therapy and chemotherapy is the
standard for limited disease, while chemotherapy is the treatment for
extensive disease. Novel innovative therapies, which could include
molecular targeting agents, are needed to treat both NSCLC and SCLC.

Worldwide, more than 1.2
million people are diagnosed
each year with lung
cancer, and approximately 1.1 million
will die from the disease. In the
United States, it is estimated that in
2004, 173,770 individuals will be diagnosed
and 160,440 will die from
lung cancer.[1] Non-small-cell lung
cancer (NSCLC) accounts for approximately
80% to 85% of all cases of
diagnosed lung cancer, while smallcell
lung cancer (SCLC) accounts for
the remainder of cases. This paper
will highlight recent advances in the
treatment of both NSCLC and SCLC.
Stages of Lung Cancer
Staging of NSCLC is based on the
TNM classification. For SCLC, staging
it is divided into limited disease
(LD) or extensive disease (ED). Table
1 provides the staging of lung
cancer as well as 1-and 5-year survival
rates for each stage of disease.[2]
Non-Small-Cell Lung CancerAdjuvant Therapy
Radiation therapy (RT) and chemotherapy
have been utilized as ad-
juvant therapy following surgical resection
of NSCLC (see Table 2 for an
overview). A meta-analysis of postoperative
RT from nine phase III trials
compared postoperative RT to no
postoperative therapy in stage I to III
disease. The results demonstrated an
adverse effect of RT on survival,[3]
which was statistically significant;
55% of surgery-alone patients survived
2 years compared with 48% of
those patients receiving postoperative
radiation therapy. The dose of RT varied
from 30 to 65 Gy.
In 1995, a meta-analysis evaluating
chemotherapy as postoperative
adjuvant chemotherapy reported that
alkylating agents were detrimental to
patients while cisplatin-based chemo-
therapy produced a 13% decrease in
the risk of death (hazard ratio, 0.87;
P = .08).[4]
In 2000, the Eastern Cooperative
Oncology Group (ECOG) compared
radiation therapy (50.4 Gy) to RT plus
etoposide and cisplatin given postoperatively
to patients with stage II and
IIIA disease.[5] In both stages, there
was no difference in survival or local
recurrences whether the patient received
postoperative RT or postoperative
RT/chemotherapy. The study did
not include a surgery-alone arm.
In the randomized International Adjuvant
Lung Cancer Trial (IALT),[6]
1,867 patients with stage I to III NSCLC
received either adjuvant cisplatin-based
CT or no therapy postoperatively. There
was an absolute 4% 5-year survival
(P < .03) advantage for those receiving
chemotherapy (44.5% vs 40.4%).
Disease-free survival (39% vs 34%)
was also significantly different at 5
years (P < .003). Age, gender, performance
status, type of surgery, or use
of RT had no effect on survival.
Neoadjuvant Therapy
Neoadjuvant CT in resectable
NSCLC appears to improve survival
rates (Table 3).[7-10] In three small
studies involving 60 stage IIIA or less
patients, there was a statistical surviv
al
advantage in patients receiving preoperative
chemotherapy.[7-9] Pass et
al reported a 3-year survival advantage
of 40% vs 12% and median survival
of 28.7 vs 15.6 months
(P = .095). Roth et al[8] demonstrated
a 3-year survival of 56% vs 15%
and median survival of 64 months vs
11 months (P = .008). Rosell et al[9]
reported a 3-year survival of 23% vs
0% and median survival of 26 vs 8
months (P < .001).
In a large neoadjuvant chemotherapy
study of 355 stage IB and IIIA
patients, Depierre et al reported a statistically
significant survival advantage
for patients with stage I and II
disease receiving neoadjuvant chemotherapy
(2-year survival, 52% vs 41%;
P = .04).[10] For stage III disease,
there was no statistically significant
difference.
Chemotherapy/RT for
Unresectable Stage III Disease
Neoadjuvant chemotherapy followed
by RT for stage III NSCLC has
been shown to be superior to RT given
alone.[11,12] Dillman et al reported
that two cycles of cisplatin plus
vinblastine followed by RT (60 Gy)
vs RT (60 Gy) alone produced a median
survival of 13.8 vs 9.7 months
with a 7-year survival of 13% vs 6%.
A phase III Intergroup study utilizing
the regimens in the Dillman et al study
plus a third arm involving hyperfractionated
RT demonstrated a statistically
significant advantage of
chemotherapy/RT over RT alone
(1-year survival, 59% vs 46%; 5-year
survival, 8% vs 5%).[13]
It appears that concurrent chemoradiation
therapy is more effective
than sequential therapy in the treatment
of unresectable stage III NSCLC
(Table 4).[14,15]
Furuse et al reported that concurrent
mitomycin (Mutamycin), vindesine,
and cisplatin (MVP) 2 + RT
28 Gy followed by 2 weeks rest and
then RT 28 Gy is statistically significantly
better than sequential MVP 2
followed by RT (56 Gy) in unresectable
stage III NSCLC.[14] The median
survival was 16.5 vs 13.3 months;
5-year survival was 16% vs 8.9%
(P = .01).
The Radiation Therapy Oncology
Group (RTOG) conducted a phase III
study comparing concurrent with sequential
chemotherapy/RT as well as
concurrent chemotherapy with hyperfractionated
RT.[15] For the concurrent
chemotherapy/RT vs sequential
therapy, median survival was 17.0 vs
14.6 months, and 4-year survival was
21% vs 12% (P = .046). However,
grade 3/4 esophagitis was 25% with
concurrent therapy but only 4% with
sequential therapy.
Stage IIIB/Stage IV Disease
Combination chemotherapy is currently
the standard treatment for good
performance patients with stage IIIB
(pleural effusion)/stage IV NSCLC.
A meta-analysis from 52 randomized
clinical trials demonstrated a survival
advantage for advanced NSCLC patients
receiving chemotherapy.[4]
The increase in median survival
was 2 months, with a 10% increase in
1-year survival. A number of twoagent
combinations are active against
advanced NSCLC.[16-20] Active
agents such as paclitaxel, docetaxel
(Taxotere), gemcitabine (Gemzar), vinorelbine
(Navelbine), and irinotecan
(Camptosar) have been combined with
cisplatin or carboplatin to treat patients
with advanced NSCLC (Table 5).
In general, such two-agent combinations
produce response rates of 20%
to 50%, median survivals of 8 to 10
months, 1- and 2-year survival rates
of 30% to 35% and 10% to 15%,
respectively.
The use of chemotherapy is effective
in treating the elderly with
NSCLC (Table 6).[21,22] In the Elderly
Lung Cancer Vinorelbine Italian
Study (ELVIS) trial,[21] untreated
stage IIIB/IV patients ≥ 70 years of
age were randomized to receive vinorelbine
or no therapy. Median survival
and 1-year survival in patients
receiving chemotherapy compared
with observation was 6.5 months and
32% vs 4.9 months and 14%, respectively
(P = .03).[21] Other studies have
shown that chemotherapy can be given
to the elderly.[22]
In the United States, docetaxel is
approved for use as second-line therapy
for patients with advanced
NSCLC.[23] Hanna et al recently reported
on pemetrexed (Alimta) compared
with docetaxel as second-line
therapy.[24] The response rate and
survival rates were similar; however,
pemetrexed was less toxic (Table 7).
To improve the therapy of patients
with NSCLC, new agents with unique
mechanisms of action are being evaluated.
Targeted therapies are such
agents.[25,26] Inhibitors of epidermal
growth factor receptors (EGFR) such
as gefitinib (Iressa) have been studied
(Table 8).[26] While gefitinib has been
shown to be effective in advanced
NSCLC patients who previously failed
one or more regimens,[27,28] when
combined with chemotherapy, there
was no advantage to those patients
receiving chemotherapy alone.[29] As
second- or third-line therapy, the response
rate was 9% to 20%, with survival
rates of 7 to 8 months. The major
toxicity has been acneiform rash and
diarrhea. Gefitinib was first approved
for use in Japan. Less than 1% of
patients receiving the drug developed
pulmonary interstitial disease. Other
molecular targeted therapies including
bevacizumab and cetuximab are
being studied.[30,31]
Small-Cell Lung Cancer
Small-cell lung cancer accounts for
15% to 20% of lung cancer diagnosed
in the United States. Small-cell lung
cancer is divided into limited disease
(LD) or extensive disease (ED). The
cornerstone of treatment of SCLC is
chemotherapy. LD SCLC is treated
with chemotherapy and radiation therapy.[
32] The 5-year survival rates with
appropriate therapy are 15% to 25%.
The use of hyperfractionated (twicedaily)
radiation therapy with chemotherapy
appears superior to that used
with daily radiation therapy.[33] However,
Schild et al reported results of a
phase III study that showed splitcourse,
twice-daily RT was not superior
to once-a-day RT in LD SCLC
(Table 9).[34]
In ED SCLC, median survival is 8
to 10 months with chemotherapy. Etoposide/
carboplatin (Paraplatin) is as
effective as etoposide/cisplatin in
treating patients with ED SCLC.[35]
More recently, irinotecan/cisplatin
was shown to be superior to etoposide/
cisplatin in patients with ED
SCLC (Table 10).[36]
For relapsed SCLC, chemotherapy
is more effective in patients who
have sensitive rather than refractory
disease (Table 10).[37]
Conclusions
Since 1990, progress, albeit modest,
has been made in the treatment of
lung cancer, especially NSCLC. Combined-
modality therapy is now used
in resectable (stage I to III) as well as
locally advanced unresectable (stage
III) disease. Adjuvant chemotherapy
produced an absolute 5% survival advantage
for patients with surgically resectable
stage I to III disease.
Chemotherapy plus RT is standard therapy
for locally advanced unresectable
NSCLC. Concurrent chemotherapy/RT
appears more effective than sequential
chemotherapy and RT in treating
such disease. Newer agents used in
combination chemotherapy have improved
survival and quality of life in
NSCLC patients with metastatic disease.
With the availability of molecular
targeted therapies, treatment of
such patients appears promising.
Some progress has been made in
the treatment of SCLC. Chemotherapy
remains the cornerstone of therapy.
In LD SCLC, concurrent
chemotherapy/RT is the treatment of
choice. For ED SCLC patients, irinotecan
plus cisplatin appears more effective
than the standard therapy of
etoposide plus cisplatin.

Disclosures

Dr. Ettinger has received
grant/research support from Aventis and
Eli Lilly. He has received honoraria from and
acted as a consultant for AstraZeneca, Aventis,
Bristol-Myers Squibb, Eli Lilly, GSK, Merck,
MGI Pharma, and Pfizer. He has acted as a consultant
for Cell Therapeutics.